About Dr. Zhong

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Research Focus

The primary focus of our laboratory is to delineate the molecular mechanisms that drive and direct axon growth, connectivity and regeneration in vivo.

In mammalian embryos, axons grow vigorously and precisely to interconnect the nervous system, and form connections to sensory receptors, to muscles and to internal organs. In the mature nervous system, axon growth stops. After an injury, axons do regenerate (if imperfectly) in the peripheral nervous system, but no productive regeneration occurs in the central nervous system. Because of this lack of axon regeneration, spinal cord injuries, for example, result in permanent paralysis, and retinal axon degeneration in glaucoma causes irreversible loss of vision.

Two reasons have been suggested for why axons cannot re-grow in the mature CNS. First, cell-intrinsic growth pathways are downregulated as the nervous system matures, and second, the mature CNS expresses surface molecules that inhibit axon growth and thereby stabilize the mature configuration. Previous work has clearly shown that injured adult neurons in the CNS can in principle re-grow axons under certain circumstances. However, such axonal regrowth or sprouting have not been able to reach their targets due to limited length and density of regenerative growth.

Our current major focus is to attempt driving axon regeneration in the injured optic nerve, which is a part of the CNS, by genetic activation in mature retinal neurons of pathways that we know can drive axon growth in embryonic neurons. We use several lines of genetically modified mice that allow us to selectively activate or inactivate specific signaling molecules in the nervous system shortly before nerve injury. We then assess regeneration phenotypes using high-resolution imaging, and we test for possible recovery of visual behaviors.

Additional current projects in our lab include the development of novel "transsynaptic tracer mice" that would enables us to visualize the entire network of neurons connected to an initial neuron or a population of neurons of interest, and to modulate gene activity in these neurons. This mouse model will be useful for a number of purposes, for example for the delineation of neuropathic pain circuitry, or to document axon regrowth and rewiring in a regeneration context.

Finally, we have developed several mouse models which mimic the neuronal aspects of human Neuro-Cardio-Facio-Cutaneous Syndromes (NCFCS). We plan to use these mice to devise and test possible therapeutic strategies targeting the very diverse symptoms associated with NCFCS.

Biography

Dr. Zhong received his Ph.D. (Dr. rer. nat) from the Ruhr University Bochum, Germany, in 1997. He conducted postdoctoral research in the laboratories of Dr. Paul Patterson (Caltech, Pasadena, CA) and Dr. Bill Snider (University of North Carolina, Chapel Hill, NC). Dr. Zhong is an ad hoc reviewer for Nature Neuroscience, Neuron, Journal of Neuroscience, EMBO Reports and European Journal of Neuroscience as well as for the NIH "Neural Differentiation, Plasticity, Regeneration, and Rhythmicity (NDPR)" and "Cellular and Molecular Biology of Glia (CMBG)" study sections.

Current Projects

Identification of RAF Downstream Effectors that Drive Axon GrowthWe have recently identified the B-RAF kinase signaling as a key player in embryonic axon growth signaling, and are testing B-RAF as a possible driver of regenerative growth. To identify the effectors that mediate B-RAF dependent growth, we mate B-RAF gain-of-function mice with mice carrying effector loss-of-function alleles, and analyze axon growth in the offspring. To complement this approach, we also screen gene expression specifically induced or suppressed by B-RAF in nervous system tissues.

Development of a Novel Transsynatic Tracer Mouse LineThe reliable tracing of axonal connections is essential for any deeper understanding of nervous system function. Many tracing methods are available, but none allow reliable tracing beyond the second synaptic connection in vivo. We have designed a genetic strategy to enable multi-synaptic tracing of axonal connectivity in vivo, starting with any given neuron or neuron population of interest.

Mouse Models for Neuro-Cardio-Facio-Cutaneous Syndromes (NCFCS)The NCFCS, which include Leopard Syndrome, Noonan Syndrome and Neurofibromatosis type I, are linked to loss- and gain-of function mutations in the RAF signaling pathway. We have observed phenotypes reminiscent of NCFCS in several of our mouse lines that carry RAF-related genetic manipulations. We are investigating and comparing these phenotypes in depth, and devising genetic strategies to counteract the NCFCS-like symptoms in vivo.